Native hyaluronan (HA) is ubiquitous in its tissue distribution and in its high molecular form has anti-inflammatory properties [1-3]. HA fragments, which are produced as a result of tissue stress and oxygen/nitrogen free radical formation, function as pro-inflammatory Danger Associated Molecular Pattern molecules (DAMP) that interact with HA receptors and Toll-like receptors to promote monocyte maturation into macrophages, macrophage chemotaxis, and production of pro-inflammatory chemokines and iNOS [1, 2, 4]. Both CD44 and RHAMM (Receptor for Hyaluronan-Mediated Motility) have been functionally linked to Toll Like receptors 2 or 4 in the regulation of these macrophage functions [5-8]. Although CD44 clearly plays a key role in pro-inflammatory responses, CD44 is ubiquitous in its expression increasing the possibility of off target adverse effects [9] and its complex mechanisms for binding to HA present challenges [10, 11] to the design of antagonists. Collectively, these have limited the use of CD44 as a clinical target. In contrast to CD44, RHAMM is not constitutively expressed in most homeostatic tissues. Instead, RHAMM expression and in particular its cell surface display occurs transiently following tissue injury but is chronic in diseases involving sustained inflammation [3]. Not unexpectedly, the safety profile for RHAMM peptides is therefore good [12, 13]. Furthermore, HA binding to RHAMM, which occurs over a short sequence and depends on ionic interactions [14], is readily competed with peptide mimics.
Shorter versions of RHAMM have been proposed as pharmaceutically relevant peptides. However, it is well known that short linear peptides containing only natural L amino acids have very limited stability against protease hydrolysis in vivo.